Vaccination strategies have been used for decades primarily to foster a protective immunity to protect patients from developing a disease after contact with an infectious agent. To this end live attenuated, dead or disrupted pathogens, pathogen preparations, or purified or recombinant components of the pathogens have been administered to patients to elicit a specific immune response to antigenic components of the respective pathogen. The components, which stimulate such an immune response can be, for example, pathogen specific proteins, polysaccharides or lipids. The specific immune response against antigens comprised within pathogens can be further stimulated by the co-administration of adjuvants. Adjuvants are known in the art to accelerate, prolong, or enhance the quality of the specific immune response to the antigen or antigens and are currently employed as part of vaccines. The proposed advantages of adjuvants include their ability to: 1) direct and optimize immune responses that are appropriate for the vaccine; 2) enable mucosal delivery of vaccines; 3) promote cell-mediated immune response; 4) enhance the immunogenicity of weaker immunogens such as highly purified or recombinant antigens; 5) reduce the amount of antigen or the frequency of immunization required to provide protective immunity; 6) improve efficacy of vaccines in individuals with reduced or weakened immune responses such as newborns, the aged, and immunocompromized patients.
Adjuvants have diverse mechanisms of action. One set of adjuvants act through toll-like receptors. Toll-like receptors (TLR) recognize specific patterns of microbial components, especially those from pathogens, and regulate the activation of both innate and adaptive immunity. Immature dendritic cells mature in response to these microbial components. As of yet, 13 members of the TLR-family have been identified. TLR are expressed by phagocytic cells such as monocytes, macrophages and dendritic cells. TLR activation through ligand binding leads to signal transduction events either in a MyD88-dependent pathway (NF-[kappa]β) or MyD88-independent pathway (IFR-3). A known lipopeptide adjuvant which interacts with toll-like receptor 2 (TLR2) is the so-called Pam3Cys-lipopeptide. According to Renate Spohn et al. (Vaccine 22 (2004) 2494-2499), the Pam3Cys-SK4 (SEQ ID NO: 11) variant was found to be the most effective additive for electing a cellular immune response in mice. Another advantage of Pam3Cys-SK4 (SEQ ID NO: 11) is that it is chemically stable and can be produced in large quantities at high quality. A Pam3Cys-lipopeptide, Pam3Cys-Ser-(Lys)4(Aca-Aca-Biotin).2trifluoroacetate (SEQ ID NO: 27) is commercially available from for example Enzo Life Sciences International Inc, Plymouth Meeting, Pa., USA for use as an adjuvant.
WO-A-2009/072767 describes the use of a mixture of the Pam3Cys-SK4 (SEQ ID NO: 11) and polyinosinic: polycytidylic acid as adjuvant for a vaccine.
The object of the present invention is to improve the immune response of a Pam3Cys-like lipopeptide.